Background Cognitive aging is associated with impaired episodic memory formation (Small et al., 1999), which requires the neurocomputational process of pattern separation to disambiguate similar stimulus input. Pattern separation relies on the dentate gyrus (DG) (Yassa & Stark, 2011), a hippocampal subfield that is susceptible to age‐related change (Small et al., 2011). Cognitive aging is also associated with impaired performance on putative measures of behavioral pattern separation (Yassa et al., 2010), called mnemonic discrimination tasks in humans. Prior work using high‐resolution fMRI suggests that age‐related impairments in mnemonic discrimination are linked to aberrant activation patterns in the DG/CA3 (Yassa et al., 2010). Whereas aging is associated with impaired DG integrity and mnemonic discrimination ability, cardiorespiratory fitness is associated with enhanced DG integrity and improved mnemonic discrimination ability. Given that cardiorespiratory fitness has been positively linked to DG/CA3 integrity in young adults (Nauer et al., 2019), it is conceivable that in older adults, cardiorespiratory fitness will modulate age‐related changes in DG/CA3 activation, which in turn, will dampen age‐related impairments in mnemonic discrimination. Methods 18 older adults (55‐85 years) and 18 young adults (18‐35 years) underwent a submaximal treadmill test to estimate cardiorespiratory fitness and high‐resolution fMRI to examine hippocampal subfield BOLD signal during encoding and retrieval of a mnemonic discrimination task (MDT). Results In older adults, we found increased right DG/CA3 BOLD signal in incorrect mnemonic discrimination trials contrasted with correct mnemonic discrimination trials, specifically during stimulus retrieval. Additionally, in both young and older adults, we found that right DG/CA3 BOLD signal in the mnemonic discrimination fMRI contrast during stimulus encoding marginally significantly predicted MDT corrected accuracy. Finally, in both young and older adults, fitness significantly negatively predicted left DG/CA3 BOLD signal in the mnemonic discrimination fMRI contrast during stimulus retrieval. Conclusions These results suggest that DG/CA3 BOLD signal relates to performance on a MDT designed to tax pattern separation, and that cardiorespiratory fitness modulates BOLD signal in these subregions. Altogether, these results suggest a link between fitness, DG/CA3 functional integrity, and mnemonic discrimination that may be critical to understanding how to dampen age‐related impairments in episodic memory.
Cognitive aging is associated with reduced integrity of the medial temporal lobe memory system. A key facet of episodic memory that demonstrates behavioral impairment with aging is pattern separation (PS), or the disambiguation of similar stimuli during neural encoding. PS is supported by the dentate gyrus (DG), a subfield of the hippocampus that demonstrates striking plasticity in response to exercise. Recent work from our laboratory has demonstrated that increasing cardiorespiratory fitness (CRF) through exercise training is associated with increased left anterior DG/CA3 volume and improved PS task performance in young adults. However, how these variables interact in cognitive aging is unknown, yet critical, given that aging is associated with impairments in hippocampal plasticity and PS task performance. Based on our findings in young adults, we predicted that CRF would positively correlate with DG/CA3 volume and PS task performance in older adults. Secondly, given the suggested role of the DG in PS task performance in humans, we predicted that DG/CA3 volume would significantly correlate with PS task performance. Sixty‐four participants aged 55–85 years underwent a submaximal treadmill test to estimate maximal oxygen uptake (VO2MAX), which operationally defined CRF, an MRI scan to examine volume of the hippocampal subfields, and a behavioral task designed to tax PS at parametrically varying levels of stimulus similarity (10, 30, 50%). There was a significant effect of similarity on PS task performance, with participants demonstrating lowest task accuracy in the condition theoretically placing the highest taxation on PS (50%). Left DG/CA3 body volume significantly predicted performance in the 50% condition. However, there was no relationship between CRF and PS task performance. Furthermore, while CRF did not predict DG/CA3 volume, it did significantly predict right and left subiculum volume, which may be unique to female participants between the ages of 60–80 years. Altogether, these findings provide support for a role of the DG in PS in older adults and suggest a relationship between CRF and hippocampal subfield volume that may be unique to the bilateral subiculum in female older adults. Support or Funding Information This work was supported by NIH grant R00 AG036845 (Schon), R21 AG049968 (Schon), and the BU Clinical and Translational Science Institute (1UL1TR001430).
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